Angiotensin converting enzyme inhibitors are effective antihypertensive drugs and also have preventive effects on the development into cardiac insufficiency and hypertrophy of the heart in hypertensive disease. Therefore, these drugs have been extensively used in the world as one of the first choice drugs for the treatment of hypertension and are very highly useful medicaments.
However, the angiotensin converting enzyme inhibitors, for example, captopril and enalapril have been reported to cause dry coughing as one of their side effects with an incidence of 15-20% and 10-33%, respectively (Arch. Intern. Med., Vol. 145, p. 1524 (1985); Arch. Intern. Med., Vol. 148, p. 249(1988); American Heart Journal, Vol. 116, p. 1658(1988); N. Z. Med. J., Vol. 100, pp. 161-163 (1987); British Medical Journal, Vol. 294, pp. 1521-1523 (1987); British Medical Journal, Vol. 299, pp. 12-16 (1989)). Thus, the use of these drugs become impossible in many patients from the above reason, and the treatment for hypertension in such patients is not sufficient.
Accordingly, in the use of highly useful angiotensin converting enzyme inhibitors, it has been greatly desired to develop drugs which depress dry coughing as the side-effect, preferably, without attenuation of their antihypertensive effects.
For resolving this problem, many studies to alleviate the dry coughing have been carried out. However, the mechanism of dry coughing induced by angiotensin converting enzyme inhibitors has not been clearly elucidated yet.
Up to date, it has been advocated as one of the mechanism of the dry coughing induction that bradykinin which accumulates in the process of the conversion of angiotensin I into angiotensin II by angiotensin converting enzyme causes the release of tachykinins (substance P, neurokinin A), and then, the tachykinins stimulate the c-fibers whose activation causes coughing (British Medical Journal, Vol. 294, pp. 1521-1523 (1987); British Medical Journal, Vol. 299, pp. 12-16 (1989); J. Appl. Physiol., Vol. 48, pp. 511-517 (1980); Nature, Vol. 264, pp. 451-453 (1976)).
On the other hand, it has been reported that sulindac, indomethacin and sodium cromoglycate (Intal.RTM.) depressed the dry coughing (THE LANCET, p. 872 (1987); Journal of Cardiovascular Pharmacology, Vol. 19, No. 15, pp. 670-673 (1992); THE LANCET, Vol. 345, pp. 13-16 (1995)). It is also known that indomethacin attenuated the antihypertensive effects of angiotensin converting enzyme inhibitors in patients with essential hypertension (Journal of Hypertension, Vol. 5, pp. 121-128 (1987)). Furthermore, the use of conventional antitussive remedy was not effective in dry coughing caused by angiotensin converting enzyme inhibitors.
Although studies to develop drugs effective in depressing dry coughing caused by angiotensin converting enzyme inhibitors are being eagerly promoted, such drugs which can be put to practical use have not been found.